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MOv18 – opening a new front for immunotherapy

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by Cancer Research UK | In depth

12 December 2023

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Antibody

Parasites, allergy and innovation – the journey to get the first IgE anti-cancer drug into a human was certainly not easy. Here we follow Sophia Karagiannis and James Spicer on an immunological adventure as they work with our Centre for Drug Discovery on this potentially ground-breaking new class of drug.


Had you been riding the Thames River ferry to London Bridge Pier on September 23rd 2008, you might have seen a man and a woman devouring a huge bar of chocolate – talking, decompressing and attempting to process the rather intense meeting they had just left.

Sophia Karagiannis – then a senior research fellow at Kings College yet to secure her first permanent academic position – and James Spicer – the head of a relatively new clinical trials unit at King’s – were returning to Guy’s Hospital having just discussed their grant application with the New Agents Committee at CRUK’s Centre for Drug Development (CDD).

Karagiannis had misunderstood the nature of the meeting. She had thought she and Spicer were going for an informal chat about their work. But no. “It was 26 very senior people,” recalls Karagiannis. “And they were all firing questions at me!”

Spicer, who would later serve on this committee, says that the quality of this review stage is a great strength of the CDD. It ensures that the department picks up new therapeutic strategies that are innovative – and sometimes frankly leftfield – yet robust. Even so, Karagiannis’s ideas were considered discomfortingly high-risk.

An allergic dream

Karagiannis had trained in a lab that transformed the understanding of allergy – and which had no history of working on cancer. But a seed had germinated there. And after a decade of pre-clinical experiments, Karagiannis wanted CRUK to back her dream of using antibodies of the type that normally trigger allergic reactions to treat cancer in people.

IgG antibodies defend against infections. Whereas allergic reactions – from rashes to potentially fatal anaphylactic shock – are mediated by immunoglobulin E antibodies. And it was IgE that Karagiannis was proposing using.

By the time of this 2008 meeting, antibodies that bind specific antigens on cancer cells, causing recipients’ immune system to attack and destroy them, had become powerful treatment options for certain cancer types. And such antibodies have continued to emerge ever since. But all these therapies use immunoglobulin G antibodies.

IgG antibodies defend against infections. Whereas allergic reactions – from rashes to potentially fatal anaphylactic shock – are mediated by immunoglobulin E antibodies. And it was IgE that Karagiannis was proposing using.

She had shown in various mouse models that IgE is more potent than IgG at shrinking tumours. But those mice were immunocompromised. Surely giving a person with cancer an injection of IgE risked a huge, potentially fatal, allergic reaction?

Sophia
Sophia Karagiannis is Professor of Translational Cancer Immunology and Immunotherapy at King’s College London

“They were firing immunological and mechanistic questions at me,” says Karagiannis. To defend her proposal, she dug into the biology of allergic reactions and explained why many fears about giving someone IgE were founded on misunderstandings about how allergies work. “At the end,” she says, “James and I came out and we bought the biggest bar of chocolate I have ever seen.”

When the feedback came, however, Karagiannis learnt that she had impressed the panel. “They told us. ‘The committee wants to take it to the next level.’”

It would still take the CDD, Spicer and her seven more years to gather the data needed to approve a human trial.

But now, fifteen years on – and over quarter of century since this project began ­– the team has just published the results of the first ever clinical trial to administer an IgE to humans.

The CRUK-sponsored study – involving people with advanced gynecological cancers – showed that when combined with the right screening tests, this novel class of drug can safely be given to humans.

In one recipient, a markedly low dose of antibody showed clear signs of shrinking her tumour.

Spicer says the reason CRUK wanted to originally sponsor this work was that he and Karagiannis weren’t simply pitching a new cancer target, they were pitching a new type of drug.  Simply proposing a new target, he says, “was not going to open up a new hinterland of translational biology in the way that this trial has.”

Bispecific antibody colored heavy chain in green and pink, light chain blue and yellow against gray background; glycosylated bispecific immunoglobulin engineered to target different antigens 3d render

Parasites, and the power of E

Karagiannis’s PhD supervisor was Hannah Gould, who cloned an IgE gene in 1982 then went on to become a world leader in allergy. As Gould’s lab deciphered IgE’s pivotal role in this maladaptive process, other groups showed this antibody type is also instrumental in defending against parasites, such as worms.

“This is something IgE does naturally,” says Karagiannis. “The immune system in the gut, in our muscles, in skin, can kill big parasites. It can really destroy them.”

But in the mid-1990s Gould’s interest in cancer was sparked by the emergence of monoclonal IgG antibodies as drugs, coupled with her keen appreciation of how IgE and IgG differ.

To trigger the destruction of an invading pathogen – or a cancer cell – antibodies must bind two things. Their antigen-binding domains must stick to proteins that distinguish the target. And their Fc domains must bind and activate receptors on the immune cells that will attack that target.

The existence of a high-affinity Fc receptor for IgE means these antibodies bind to immune cells much more avidly than IgG does. This causes sustained immune activation – plus maximal activation by only tiny amounts of IgE.

Additionally, allergy studies had shown that compared to IgG, IgE powerfully recruits a different set of effector cells – cells that Gould thought would be more effective at destroying cancer cells, especially in solid tumours.

In a departure from her established research interests, Gould asked her lab to run some pilot experiments to test these ideas.

Choosing to work on a model of ovarian cancer, the lab acquired an existing IgG, called MOv18. This antibody bound folate receptor alpha, an antigen that characterizes this tumour type, and it was known to have anti-cancer activity. Then, her lab made an IgE version of MOv18 and compared the two.

In the pivotal experiment, Gould’s team grew tumours in mice using an ovarian cancer cell line, then treated these animals with either MOv18-IgG or MOv18-IgE.

IgE shrank tumours more – and for longer.

While various lab members conducted these initial experiments, Karagiannis was completing her PhD on allergy. But then Gould asked her to take over the project. “I was the hired person to get that study over the line,” Karagiannis says. “Hannah considered me the person to move it forward.”

They published their first results in 1999, then Karagiannis developed the next model in which to test MOv18-IgE – from now on, simply MOv18. Using xenografts of patient-derived cancers implanted in mice, the results were the same: IgE was a much more potent anti-cancer agent than IgG.

But despite the lab’s excitement, funding was hard to come by. So much so, Karagiannis had to leave the lab in 2002 and take a job in industry. Her work there convinced her of the value of immunotherapies for cancer, but her heart remained with academia and IgE.

And when funding materialised in 2003, Gould invited Karagianis back. “Hannah said, ‘I’m giving you a postdoc but you’re not just coming for a postdoc. I’m going to look after you. You can take this on for your career’,” says Karagiannis. “Because Hannah’s lab was all about allergy and they didn’t want to diversify, she saw me as the person from the beginning. In many ways, Hannah believed in me more than I believed in me.”

Building the case

In late 2003, Karagiannis published the lab’s second paper on MOv18 describing the results in the xenograft model. Then, she worked on uncovering the mechanisms by which IgE induced the eradication of tumours. Papers in 2007  and 2008  confirmed that IgE recruits a unique set of immune cells and that activated monocytes are central.

This work helped Karagiannis secure a fellowship in 2007, which allowed her to begin transitioning to her own lab – and to focus on moving this work toward the clinic. Equally significantly, Spicer had joined King’s, and he and Karagiannis had instantly clicked.

James Spicer
James Spicer is Professor of Experimental Cancer Medicine within the Comprehensive Cancer Centre at King’s College London. and a consultant in medical oncology at Guy's and St Thomas' NHS Foundation Trust.

A medical oncologist, Spicer was hired by King’s and its sister hospitals in 2006, “to set up a phase one unit pretty much from scratch.” And Karagiannis’s work was exactly the type of project Spicer was there to advance.

“We bonded very quickly from an intellectual point of view,” Spicer says. “And we became friends over the years — almost inevitably, given everything that we went through together.”

Advising Karagiannis on the pre-clinical data needed to assemble a sound clinical trial application, Spicer quickly became familiar with the issues that swirled around this project. Grant applications based purely on pre-clinical work, he says, invited criticism because “people started to be excessively concerned about safety. And whether we would ever be able to deliver an IgE drug without killing people with toxicities like anaphylaxis.”

“Industry,” he says, “was either afraid of this or didn’t understand.”

It is innovative projects exactly like this which CRUK, in general, and the Drug Development Unit, in particular, are set up to support. Even so, Sarah Mellor, who became the CDD’s project manager of MOv18 in 2010, says, “it was a big thing for us to decide to do it because nobody else would touch it with a bargepole.”

Mellor also says that by the CDD’s normal standards, “It came in at a very early stage.”

“But it was seen as a real potential game changer,” she says. “If we could do it, it would be a really significant step forward in cancer research. That was the real hook for doing the project.”

Getting to the clinic

Nigel Blackburn – who this autumn retired as director of the CDD – recently wrote that when he became leader of the unit in March 2009, he was immediately tasked with streamlining the department by drastically reducing the number of projects it supported – and that an air of scepticism still clung to IgE. On top of safety concerns, this being an entirely new class of therapeutic antibody meant that nobody had ever made clinical grade IgE before.

Blackburn credited a “small core of people in the department” with convincing him of the project’s merit and he pressed ahead with it. Looking back, Karagiannis says, “Clearly, Nigel fought our corner in a big way.”

Regarding manufacture, Mellor says, “It had to be done to a certain standard in order to satisfy the regulators,” so CDD took the lead on this, using CRUK’s in-house production facilities.

“My worst nightmare would have been that we would have had material produced that was perfectly good quality, but was inactive,” says Karagiannis.

Thankfully, the methods used for producing clinical-grade IgG largely applied to making high quality IgE, meaning CRUK could make IgE suitable for use in people – assuming that is, those antibodies could pass all the necessary safety and toxicology tests.

And this presented another potential banana skin.

As new drugs approach the clinic, it’s commonly demanded that they are tested in animals as closely related to humans as ethically possibly. But CRUK has a hard rule that it does not conduct research in non-human primates.

Once more, this set people on edge. But again, Karagiannis’s expertise in immunology was critical.

What’s fundamental for testing immunological drugs in animal models is not the evolutionary distance between the model species and humans, it is whether the antibody -reacts with its target antigen in both species. Therefore, Karagiannis wrote to a research facility that routinely worked with monkeys and requested some blood samples. The facility obliged – and when Karagiannis’s lab tested MOv18, they found inadequate cross-reactivity. Testing it in monkeys would be futile. If the antibody appeared to be safe in them, this could be an extremely dangerous false-negative.

Instead, experiments by Karagiannis – and by others in the field – showed that the IgE system of rats operates very similarly to that of humans. Therefore, she proposed creating a rat version of MOv18 and to do toxicology screening in these rodents.

Karagiannis says she made her case to the MHRA, in a four-and-a-half hour-long meeting, again basing her arguments on meticulous immunological reasoning. And once the MHRA consulted a specialist panel, they agreed to Karagiannis’s plan.

antibodies

Deborah Josephs – then a clinical research fellow and now a Phase 1 investigator with Spicer –spearheaded the work that showed MOv18 was safe in rats, so likely safe in people and working closely with a contract research organization chosen by the CDD her data on safety were formally confirmed and therefore suitable for submission to the MHRA.

But Josephs didn’t only study toxicology. Using a cancer model in rats, she tested both safety and efficacy. And for good measure, further dissected the drug’s mode of action.

Gould and Karagiannis had always thought IgE could be safely used in cancer patients, because allergic reactions are triggered by IgE being activated by circulating, multivalent complexes of an allergen. And although tumours shedding large amounts of an antigen into the bloodstream could risk such a reaction, in the tumours being targeted, the antigen was mainly stuck to the cells’ surfaces – and if it was shed, it wasn’t in multivalent complexes.

Josephs research confirmed that MOv18’s tumour-destroying action does not mimic allergy.

“What we think we’re doing is waking up that part of the immune response that targets parasites,” says Karagiannis. In the case of an IgE antibody directed against tumours, this mechanism is critically dependent on activating macrophages within the cancer, and it involves the release of a distinctive profile of cytokines and other inflammatory messengers.

In fact, when the group looked at the survival rates of people with ovarian cancer, they saw that those individuals who had higher levels of these particular cytokines, lived longer. Thus, suggesting that intrinsic activation of an IgE immune response was naturally protective.

Of Josephs’ work, Spicer says, “To generate safety and efficacy data was a lot of experiments all rolled into one. There’s always a sort of killer experiment which gets you over the edge towards the clinic. And that was the data that really got us home and dry with the MHRA, the regulator.”

Finally, a trial

The CDD and King’s teams assembled a clinical trial application jointly and went together to defend it at the MHRA. The trial was approved in November 2015 – to run across multiple hospitals under the management of the CDD. And in February 2016, the first volunteer to ever receive an IgE drug was given MOv18.

This dose escalation study was designed primarily to test MOv18’s safety and tolerability. Across five, pandemic-disrupted years, twenty-six volunteers participated. Each had advanced or metastatic gynecological cancer: 21 were ovarian and all tumours expressed MOv18’s folate receptor alpha antigen. After treatment, participants were also screened for antitumor activity.

We've demonstrated for the first time that IgE as a therapeutic is potentially safe.

Despite their pre-clinical safety data, Mellor says, “We had to go in at a really, really low dose.” The first two volunteers received only 70 micrograms of protein. Then, the team “aggressively but safely” increased the dosage, the final two participants receiving 6 and 12 milligrams, respectively – still a relatively low dose for an antibody drug.

The official protocol safeguarded volunteers against allergic reactions by mandating skin-prick test that checked for reactions to MOv18. In parallel, however, Karagiannis’s team developed several novel new screening assays. “We put them to the test in the trial,” she says, “We didn’t know which would parallel the clinical picture.”

Several people receiving MOv18 briefly developed skin rashes that could be controlled with medication. One person did, though, experience moderate anaphylaxis. The reaction was resolved in the hospital setting but is clearly undesirable.

When Karagiannis checked this person’s readouts on her new assays, she saw that before she’d received the drug, she had tested positive in one. Termed the basophil activation test, this BAT assay was then used to screen future volunteers. “It became a clinical tool,” says Karagiannis. One other person who tested positive on it was denied access to the trial.

“With a phase one trial, my priority is to study safety, and make a decision of ‘go or no- go’ based on that,” says Spicer. “We’ve demonstrated for the first time that IgE as a therapeutic is potentially safe.”

In one participant – given 700 micrograms of MOv18, a dose that Spicer calls “homeopathic from an IgG point of view” – the drug showed distinct anticancer activity.

Karagiannis was at Lisbon airport, returning from a conference, when Spicer called and asked if she was sitting down. He told her that this person’s tumour had shrunk, and their ascites volume had fallen along with a sharp decrease in some important cancer markers. Spicer told Karagiannis. “You know this never happens on its own. Something has happened there.”

Karagiannis suspects that some patients may have just the right complement of immune cells and tissues conditions to allow even small amounts of a drug to have an effect. “But I think going up the doses,” she says, “there will be a dose where most people will have enough engagement of this antibody with immune cells to trigger a beneficial effect.”

The team now eagerly awaits a next trial in which doses will be elevated further.

That trial will be conducted by Epsilogen, a company that Karagiannis and Spicer co-founded in 2017.  “It was never my dream to just sit there and learn about something and then publish it and get a nice career and a nice position at a university,” says Karagiannis of this venture. “I felt that if we get a company off the ground, then there is a chance that this will be made available to everybody who’s dying of ovarian cancer today or any other cancers.”

Founded principally on the licensing of a second IgE from Kargiannis, which targets melanoma, Epsilogen also secured first refusal on MOv18 contingent on the outcomes of this trial – which it has now exercised.

“If we can get a company to take it on and take it forward, then that’s success for us,” says the CDD’s Mellor. “Our goal was to get it through to the end of phase one and pull together a package of data that was appealing to somebody.”

Spicer and Karagiannis maintain their respective academic and clinical roles while working closely with Epsilogen. Whether it is MOv18 itself or follow-on molecules, Spicer says he hopes the company will “establish a whole new therapeutic class, which is what we hope this particular trial heralds.”

What types of cancer will respond best to IgE treatment remains to be seen, says Karagiannis. “Selecting a good target that feeds the IgE biology and immunology is important,” she says. “I would go for solid tumours because there’s where IgE does its best functions, activating tissue resident immune cells.”

She hopes that IgG and IgE drugs will prove to be complementary. “We’re not here to abolish IgG in any way. We’re here to add to the toolbox we need to have for patients with cancer,” she says.

This project – 25 years in the making – has forged firm friendships between the various protagonists.

“Without CRUK,” Karagiannis says, “we would not have been where we are today, if it wasn’t for all the wonderful work we’ve done together. Even the preclinical work that we did together was pioneering and groundbreaking.”

“If we didn’t have CRUK it was going to be a bigger uphill struggle by far. And I have no idea what would have happened. CRUK took on the difficult part.”

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Liam Drew

Author

Liam Drew

Liam is a writer and journalist covering biology and medicine. In 2020, he received the Association of British Science Writers’ Award for Best Engineering and Technology Reporting.

    Comments

  • Thor
    13 December 2023

    I absolutely love this article! I would love to read more from this author.

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  • Thor
    13 December 2023

    I absolutely love this article! I would love to read more from this author.

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